Abstract

6030

Although the immune system is capable of recognizing tumor cells, it has been shown that effective anti-tumor immunity does not occur to any significant level in most advanced-stage diseases. Failure of the host to raise a successful immune defense may be attributed to insufficient and/or ineffective immune stimulation. In the present study, a potent priming antigen from Streptococcus pyogenes, Emm55, was utilized to initiate a therapeutic, neuroblastoma-specific immune response in syngeneic A/J mice. Two groups of 72 mice were inoculated with various doses of wild-type Neuro-2a cells and Neuro-2a cells transfected with emm55 (Neuro-2a/55), respectively. Of the72 mice inoculated with Neuro-2a, 64 developed tumors. Of the 72 mice inoculated with Neuro-2a/55, 2 developed tumors, but these tumors regressed completely. In a further study, 36 mice vaccinated with either 3x106 or 1x106 Neuro-2a/55 were subjected to challenge with 3x106 Neuro-2a. Of these, 8 mice developed tumors, but 2 of these tumors regressed completely. Of the 18 control mice inoculated with 3x106 Neuro-2a alone, 17 developed tumors. Immunological studies on sera and spleen cells from Neuro-2a/55-vaccinated mice showed antibody production to both Emm55 and Neuro-2a. Cell mediated Neuro-2a-specific responses were also detected. In follow-up studies, 112 syngeneic A/J mice were inoculated with 1x106 Neuro-2a. These mice were divided into 7 treatment groups. Sixteen mice received no treatment. The remaining 96 mice were divided into 6 groups of 16. Three of these 6 groups received either 1, 2 or 3 inoculations of 3x106 irradiated Neuro-2a/55 on days 3, 8 and 13, respectively. The other 3 groups received either 1, 2 or 3 inoculations of 1x106 irradiated Neuro-2a/55 on days 3, 8 and 13, respectively. Two control groups of 7 mice were given 3 doses of either 3x106 or 1x106 irradiated Neuro-2a/55 on days 3, 8 and 13. All mice receiving Neuro-2a alone developed tumors by day 15. No tumors were evident by day 83 in mice receiving Neuro-2a/55 alone. Of the 3 groups of mice receiving 3x106 irradiated Neuro-2a/55, 9 of 48 mice developed tumors (19%), whereas, 17 of 48 (35%) receiving 1x106 irradiated Neuro-2a/55 developed tumors. Thus, the Neuro-2a/55 vaccine conferred a significant therapeutic benefit to mice with this aggressive cancer. The Emm55 antigen is highly antigenic but not superantigenic or rheumatogenic like other streptococcal proteins. Its expression in the tumor cells used in this study did not produce unwanted side effects or an overblown immune response when administered to mice. It is therefore postulated that autologous human cells from tumors resistant to conventional treatments engineered to express the Emm55 antigen will not only favor a specific anti-tumor immune response but because Emm55 is a common antigen, a vaccine constructed in this way may offer the added benefit of an anamnestic response without evoking an adverse autoimmune reaction.